Project Summary Title: Comparative Genomics of Plasmodium vivax: Insights into Duffy Negative Erythrocyte Invasion Vivax malaria is the most geographically widespread human malaria, causing tremendous suffering and major negative effects on economic productivity. African blacks or people with African ancestry are thought to be protected from Plasmodium vivax infection because their lack of Duffy antigen expression on the surface of the erythrocytes renders P. vivax unable to invade the erythrocytes. While recent studies challenge this conventional wisdom, raising the possibility that that some lineages of P. vivax may have evolved to use receptors other than Duffy for erythrocyte invasion, there is scarce evidence to this notion and the intrinsic invasion mechanism is largely unknown. In this Academic Research Enhancement Award (AREA) R15 proposal, we will examine the genetic basis of erythrocyte invasion and ligand-receptor interactions of P. vivax in Duffy negative humans. There are two specific aims: 1) to identify genetic variants of Plasmodium vivax between Duffy positive and Duffy negative individuals by whole genome sequencing, and 2) to investigate the binding activity of genetic variants identified in Aim 1 and other potential erythrocyte-binding proteins in Duffy negative individuals. As our study sites in Ethiopia have a large number of P. vivax cases and a significant proportion of Duffy negative individuals, we have a unique opportunity to study the biology and transmission of P. vivax in Africa with predominantly Duffy negative individuals. This integrative, multi-disciplinary project will offer tremendous opportunities for field-based, hands-on laboratory, and bioinformatics research experiences to both undergraduate and graduate students in the Department of Biological Sciences. Moreover, this award will strengthen the research environment and inter-departmental collaborations within UNCC. The issues addressed in this application are paramount to the understanding of P. vivax epidemiology and disease burden. Some P. vivax strains could have evolved the ability to infect Duffy negative Africans and these parasites may become an emerging cause of severe disease across Africa. This research will provide genomic information of P. vivax from endemic Africa and identify alternative erythrocyte- binding ligands that allow P. vivax to infect Duffy negative individuals. Our findings may reveal novel vivax erythrocyte invasion mechanisms and will significantly advance our understanding of malaria parasite genetic variation and evolution.